DESCRIPTION: This proposal describes the framework of an Avenir DP2 grant for Alejandro B. Balazs, PhD. Dr. Balazs is currently an assistant professor at Harvard Medical School and a principal investigator at the Ragon Institute of MGH, MIT & Harvard. Dr. Balazs' research is focused on engineering the immune system via gene transfer as a novel means of creating protection against infectious disease. This proposal explores the potential for technology that Dr. Balazs has developed to express monoclonal antibodies in vivo as a long-lived therapeutic treatment for HIV infection. Preliminary results included in this proposal suggest that antibodies expressed in this manner have the potential to durably control HIV infection in a humanized mouse model of HIV therapy with a single intramuscular injection of vector. The broad goal of this proposal is to establish proof-of-principle for such a strategy to be implemented as a functional cure for HIV infection. The proposal aims to achieve this by determining the potential of various broadly neutralizing antibodies (bNAbs) to suppress ongoing viral replication. It will quantify the ease of viral escape from each bNAb in vivo and will examine the sensitivity of such escape mutants to be neutralized by other bNAbs to inform the design of combination antibody therapies. To better understand the effector mechanisms that may contribute during antibody-mediated viral suppression, this proposal seeks to quantify the contribution of innate immune interactions on long-lived viral suppression. To improve the activity of future bNAb-based strategies against HIV, mutations known to enhance effector functions will be engineered into vectored antibodies in an effort to increase their activity. The goals of this proposal are highly relevant to substance abusing populations who currently exhibit inadequate adherence to existing drug regimens and who stand to benefit from novel therapies to treat infection over long-periods of time with only a single administration. In addition, this wrk will substantially enhance our understanding of antibody-mediated HIV suppression and elucidate the effector functions capable of targeting the viral reservoir, which could contribute towards a new clinical strategy to treat HIV infection for substance abusing populations, consistent with the mission of both NIDA as well as the broader mission of the NIH.